The growing prevalence of obesity and type 2 diabetes complicates risk and clinical management by potentiating and/or exacerbating hypertension, hyperlipidemia, atherosclerosis and cardiomyopathy, leading to increasing use of the term “cardiometabolic disease” (CMD) to encompass the many facets of this complex syndrome. While several classes of drugs have been developed to manage various aspects of CMD, novel integrative therapies that target central “unifying” features of its pathogenesis and/or progression are needed to simplify clinical management, reduce risk of multi-drug interactions, and avoid potentially adverse effects, such as the effect of treatment using statin cardiovascular drugs on diabetes risk.
CMD and related disorders are thought to be associated with dietary factors. Compared to the diet of our ancestors, the modern Western diet is highly enriched with linoleic acid (LA), an essential polyunsaturated fatty acid (PUFA), due largely to increased consumption of LA-rich vegetable oils used in commercial food processing. This greater proportion of LA may contribute to the higher prevalence and onset of insulin resistance/type 2 diabetes in developed societies by increasing endogenous production of arachidonic acid (AA) and its proinflammatory eicosanoid derivatives that are key initiators and propagators of inflammatory signaling linked to the development of these conditions. However, numerous large cohort studies examining the effect of dietary n6 PUFA (LA) intake on insulin sensitivity have produced widely variable results, making unclear whether to increase, decrease, or ignore dietary intake of LA in attempting to manage metabolic risk.
Systemic low-grade inflammation is widely believed to play an important role in the pathogenesis and/or progression of all CMD-related pathologies. As described previously, excess dietary LA is thought to increase the endogenous production of arachidonic acid (AA). The metabolism of AA by cyclooxygenase (COX) and lipoxygenase (LO) enzyme pathways generates an array of pro-inflammatory eicosanoid species that are known to be centrally involved in the initiation and propagation of the inflammatory cascade. Accordingly, nearly all currently available treatments for inflammation, such as NSAIDs, target COX enzyme pathways which produce pro-inflammatory eicosanoid species such as prostaglandins and thromboxanes. AA-derived eicosanoid products of the LO enzyme pathways, such as leukotrienes and HETEs, also contribute significantly to inflammatory signaling and are implicated in cardiovascular disease, which has led to the development of several experimental LO and dual COX-LO inhibitor compounds. However, there is some concern regarding the use of these and other inhibitors of AA metabolism enzymes, as different selectivities and potencies of an inhibitor for one enzyme pathway may divert AA into another pathway, creating an imbalance in the relative distribution of species with different, or even opposing, pathogenic potentials. Therefore, the targeting of select AA metabolism enzymes as an anti-inflammatory treatment in metabolic disease and its complications is thought to be a complicated and risky approach.
Delta-6 desaturase (D6D) is a microsomal enzyme that catalyzes rate-limiting steps in the endogenous conversion of dietary LA to AA. The D6D pathway is the primary source of long-chain PUFAs present in biological membranes in the absence of dietary supplementation, therefore changes in serum and tissue D6D product/substrate ratios (e.g., AA/LA) are commonly used as indices of D6D activity in vivo. A number of epidemiological studies over the past two decades have demonstrated positive correlations between serum AA/LA ratios and CMD-related pathologies, but whether elevations in D6D activity actually cause or potentiate the development of CMD/inflammation cannot be determined from these studies. D6D hyperactivity has been recently linked to common single nucleotide polymorphisms of the D6D gene (fads2) that are strongly associated with increased incidence of type 2 diabetes, coronary artery disease and systemic low-grade inflammation. Therefore, D6D hyperactivity, resulting from a “Western” diet or genetic predisposition, could potentiate CMD by increasing endogenous conversion of dietary LA (the primary PUFA in the modern diet) to AA and its pro-inflammatory derivatives. However, the effectiveness of D6D inhibition at reducing or reversing CMD and related syndromes remains largely unknown.
Therefore, a need exists for a treatment for a cardiometabolic disease or disorder that includes administering an inhibitor of D6D. A need also exists for a method for identifying a compound as an inhibitor of D6D for use as a treatment of a cardiometabolic disease or disorder. Further, a need exists for a transgenic animal characterized by the overexpression of D6D for use in the study of the role of D6D overexpression in the progression of a cardiometabolic disease or disorder.